Biology subjects

Nichols, W.

Publications and source records attributed to Nichols, W..

3 recordsLinked to original sources

bioRxiv2024

Pulmonary primary oxysterol and bile acid synthesis as a predictor of outcomesin pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare and fatal vascular disease with heterogeneous clinical manifestations. To date, molecular determinants underlying the development of PAH and related outcomes remain poorly understood. Herein, we identify pulmonary primary oxysterol and bile acid synthesis (PPOBAS) as a previously unrecognized pathway central to PAH pathophysiology. Mass spectrometry analysis of 2,756 individuals across five independent studies revealed 51 distinct circulating metabolites that predicted PAH-related mortality and were enriched within the PPOBAS pathway. Across independent single-center PAH studies, PPOBAS pathway metabolites were also associated with multiple cardiopulmonary measures of PAH-specific pathophysiology. Furthermore, PPOBAS metabolites were found to be increased in human and rodent PAH lung tissue and specifically produced by pulmonary endothelial cells, consistent with pulmonary origin. Finally, a poly-metabolite risk score comprising 13 PPOBAS molecules was found to not only predict PAH-related mortality but also outperform current clinical risk scores. This work identifies PPOBAS as specifically altered within PAH and establishes needed prognostic biomarkers for guiding therapy in PAH. One-Sentence SummaryThis work identifies pulmonary primary oxysterol and bile acid synthesis as altered in pulmonary arterial hypertension, thus establishing a new prognostic test for this disease.

systems biology↗

bioRxiv2023

Computational Screen for Sex-Specific Drug Effects in a Cardiac Fibroblast Network Model

Heart disease is the leading cause of death in both men and women. Cardiac fibrosis is the uncontrolled accumulation of extracellular matrix proteins which can exacerbate the progression of heart failure, and there are currently no drugs approved specifically to target matrix accumulation in the heart. Computational signaling network models (SNMs) can be used to facilitate discovery of novel drug targets. However, the vast majority of SNMs are not sex-specific and/or are developed and validated using data skewed towards male in vitro and in vivo samples. Biological sex is an important consideration in cardiovascular health and drug development. In this study, we integrate a previously constructed cardiac fibroblast SNM with estrogen signaling pathways to create sex-specific SNMs. The sex-specific SNMs maintained previously high validation when compared to in vitro experimental studies in the literature. A sex-specific perturbation analysis and drug screen uncovered several potential pathways that warrant further study in the pursuit of sex-specific treatment recommendations for cardiac fibrosis. Author SummaryHeart failure is a leading cause of death for both men and women, but we still do not have adequate therapies to prevent or reverse this disease. One factor that contributes to heart failure is scarring of cardiac tissue, also known as fibrosis. Computer models can help find new heart failure drugs by simulating hundreds of biological reactions that regulate fibrosis at the molecular level. Unfortunately, the differences in male and female patients are not usually considered for these drug discovery simulations, which can result in drugs that work well for some individuals but not for other individuals. In our study, we added sex-specific biological reactions to a computer model in order to identify drugs that could treat fibrosis differently in male and female patients. Our simulations also predicted why premenopausal women may generally develop less fibrosis than men, while post-menopausal women may develop similar levels of fibrosis as men.

systems biology↗

bioRxiv2022

Nest shape influences colony organization in ants: spatial distribution and connectedness of colony members differs from that predicted by random movement and is affected by nest space

Many animals inhabit nests that protect them from adverse environments. However, the effects of living in a built or found structure are not limited to protection: the physical space can shape and organize behavior, particularly in self-organized collective systems. In addition, the geometry of nest space may not be under the animals control, raising the question whether animals can compensate for the effects that unexpected or suboptimal geometries may have. Here we examine how the shape of a nest cavity affects spatial organization of colonies in the ant Temnothorax rugatulus, a species that adapted to nest cavities of unmodifiable internal dimensions, since they inhabit rock crevices with rigid walls. We show that the emerging spatial relationships of workers, brood, queens, and young alates, as well as their relationships and distances to significant points in the nest, are all significantly influenced by nest shape, with the brood distributions most affected. However, we also found that the size of worker spatial fidelity zones, i.e. the areas in the nest that individual workers occupy and that may be key regulators of division of labor, are overall not affected by nest shape. These findings indicate that ants may actively regulate which areas of a nest they occupy, and that they may compensate for effects of nest architecture constraints. Physical properties of nests can thus influence the organization of ant colonies, highlighting the need to explore spatial constraints as a direct influence on the organization, movement, and communication of evolved or engineered self-organized systems.

animal behavior and cognition↗